A vaccine against HIV is urgently needed. The development of such vaccine represents an unprecedented challenge. The tremendous genetic diversity of HIV, for example, imposes a major obstacle for vaccine development. Furthermore, HIV infects activated CD4 T cells that are generated following vaccination or infection, suggesting that HIV feeds from the immune response that it elicits. Therefore, we propose that a viable vaccine strategy should minimize the induction of immune responses that fuel HIV and maximize immune responses that control HIV. We first would like to assess a possible detrimental role for virus-specific CD4 T cell responses and determine whether the immune dysregulation that is observed in AIDS patients has mechanistic overlaps with that observed in our model of LCMV infection in mice. We would also like to develop novel vaccine regimens that abrogate the activation of CD4 T cell responses and generate high antibody and CD8 T cell responses at sites where HIV replicates. The Aims of this application are: Aim 1. To compare the transcriptional signature of helper versus detrimental CD4 T cells following chronic LCMV infection, and compare these signatures to those of HIV infected patients. Aim 2. To ascertain the role of memory CD4 T cells following HIV infection, and assess whether a vaccine that does not induce CD4 T cell responses can provide immune protection in the humanized mouse model of HIV infection. Aim 3. To evaluate the immunogenicity of novel rLCMV vectors in mice, and develop regimens to maximize cytotoxic CD8 T cell responses in lymph nodes and gut in the complete absence of CD4 T cell priming. The findings from this K22 Career Development Award will be crucial for rational vaccine design, and may help to develop the first generation of tailored CD4-less vaccines against HIV.